349 research outputs found
Devic mouse: a spontaneous double-transgenic mouse model of human opticospinal multiple sclerosis and autoimmune T- B cell cooperation
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central
nervous system (CNS). Myelin antigen(s) specific T cells, B cells, and antibodies are thought to play a role in the pathogenesis of MS. While the influence of autoantigenspecific CD4+ T cells has been extensively studied in animal models, the relevance of autoantigen specific B cells and their interactions with pathogenic T cells are largely unknown.
The original aim of the present study was to create a new mouse model with
which to investigate the interaction of myelin autoantigen specific B and T cells and their role in MS pathogenesis. The study was further expanded to analyze the nature and triggers of spontaneous disease and similarity of the mouse lesion pattern to that in human disease.
The double-transgenic mouse (“Devic mouse”) strain presented here contains myelin oligodendrocyte glycoprotein (MOG)-specific T as well as B cells. A significant proportion (>50%) of these mice showed spontaneous experimentalautoimmune encephalomyelitis (EAE)-like disease at a young age. In contrast, all single transgenic littermates were free of clinical disease. Spontaneous EAE requires both MOG-specific T and B cells, since the breeding of MOG-specific Ig heavy chain knock-in mice with ovalbumin specific T cell receptor (TCR) transgenic mice did not develop any disease.
Histological analysis of the CNS of affected mice revealed restricted localization of lesions in the spinal cord and optic nerves as well as severe demyelination and axonal damage that spared brain and cerebellum. The inflammatory infiltrates were predominantly composed of macrophages and CD4+ T cells, but occasionally also eosinophils. This peculiar localization of the demyelinating lesions and infiltration profile differ from classic EAE and is reminiscent of Devic’s neuromyelitis optica, a variant of classic MS in humans.
It is not well understood what triggers the initiation of spontaneous EAE. The microbial environment does not significantly affect the clinical disease. Stimulation of the innate immune system with toll-like receptor (TLR) ligands or depletion of putative regulatory cells did not significantly affect EAE development. The (re-)activation of lymphocytes in sick Devic mice mainly occurs in the CNS without
evidence of priming in the peripheral lymphoid organs.
MOG-specific B and T cells cooperate by means of several mechanisms. MOGspecific
B cells, which bind MOG but not the immunodominant peptide MOG 35-55 via their surface immunoglobulin (Ig), efficiently presented even high dilutions of MOG to T cells. This resulted in the enhanced proliferation of T and B cells as well
as rapid activation. Stimulated T, but not B cells, secreted large amounts of Th1
cytokines IFNg and IL-2 along with small amounts of Th2 cytokine IL-5. In addition,
MOG-stimulated T and B cells expressed a set of co-stimulatory molecules, which
further help to modulate the proliferation and activation. Surprisingly, the doubletransgenic Devic mice, but not their single transgenic littermates, had high titers of MOG-specific IgG1 antibodies in the serum, which indicates a previous encounter with antigen in vivo. However, similar MOG-specific serum IgG1 titers were present irrespective of the clinical status. The transfer of EAE by Devic splenocytes in immunodeficient mice or by bone marrow reconstitution in wild-type mice further supported the in vivo cooperation of MOG-specific T and B cells to induce spontaneous EAE.
In summary, Devic mice show several salient features that are important for study
of the pathogenic mechanisms of CNS autoimmunity. As a model of spontaneous
autoimmunity, they may allow us to study the triggering factors of autoimmunity as
well as the factors that determine restricted infiltration of immune cells into the CNS.In addition, the model may be useful for validating novel therapies for autoimmune CNS diseases
Efficient Data Representation by Selecting Prototypes with Importance Weights
Prototypical examples that best summarizes and compactly represents an
underlying complex data distribution communicate meaningful insights to humans
in domains where simple explanations are hard to extract. In this paper we
present algorithms with strong theoretical guarantees to mine these data sets
and select prototypes a.k.a. representatives that optimally describes them. Our
work notably generalizes the recent work by Kim et al. (2016) where in addition
to selecting prototypes, we also associate non-negative weights which are
indicative of their importance. This extension provides a single coherent
framework under which both prototypes and criticisms (i.e. outliers) can be
found. Furthermore, our framework works for any symmetric positive definite
kernel thus addressing one of the key open questions laid out in Kim et al.
(2016). By establishing that our objective function enjoys a key property of
that of weak submodularity, we present a fast ProtoDash algorithm and also
derive approximation guarantees for the same. We demonstrate the efficacy of
our method on diverse domains such as retail, digit recognition (MNIST) and on
publicly available 40 health questionnaires obtained from the Center for
Disease Control (CDC) website maintained by the US Dept. of Health. We validate
the results quantitatively as well as qualitatively based on expert feedback
and recently published scientific studies on public health, thus showcasing the
power of our technique in providing actionability (for retail), utility (for
MNIST) and insight (on CDC datasets) which arguably are the hallmarks of an
effective data mining method.Comment: Accepted for publication in International Conference on Data Mining
(ICDM) 201
Signal Recovery in Perturbed Fourier Compressed Sensing
In many applications in compressed sensing, the measurement matrix is a
Fourier matrix, i.e., it measures the Fourier transform of the underlying
signal at some specified `base' frequencies , where is the
number of measurements. However due to system calibration errors, the system
may measure the Fourier transform at frequencies
that are different from the base frequencies and where
are unknown. Ignoring perturbations of this nature can lead to major errors in
signal recovery. In this paper, we present a simple but effective alternating
minimization algorithm to recover the perturbations in the frequencies \emph{in
situ} with the signal, which we assume is sparse or compressible in some known
basis. In many cases, the perturbations can be expressed
in terms of a small number of unique parameters . We demonstrate that
in such cases, the method leads to excellent quality results that are several
times better than baseline algorithms (which are based on existing off-grid
methods in the recent literature on direction of arrival (DOA) estimation,
modified to suit the computational problem in this paper). Our results are also
robust to noise in the measurement values. We also provide theoretical results
for (1) the convergence of our algorithm, and (2) the uniqueness of its
solution under some restrictions.Comment: New theortical results about uniqueness and convergence now included.
More challenging experiments now include
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